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Makoto Saito, Shinpei Harada, Reiki Ogasawara, Koh Izumiyama, Akio Mori, Masanobu Morioka, Takeshi Kondo Department of Internal Medicine and Hematology, Blood Disorders Center, Aiiku Hospital, Sapporo, JapanCorrespondence: Makoto Saito Email ikyoku@aiiku-hp.or.jpAbstract: Eculizumab has been developed as a breakthrough treatment for paroxysmal nocturnal hemoglobinuria (PNH). Not only for breakthroughs, eculizumab therapy is also known to increase the risk of invasive meningococcal infection. It has also been recently reported that, although rarely, administration of eculizumab may result in disseminated gonococcal infection (DGI). We report here a case in which a young patient who had used eculizumab for PNH developed DGI. A 22-year-old Japanese male with PNH who had been treated with eculizumab complained of high fever, mild nausea, headache and right knee joint pain. The patient was admitted and suspected to have sepsis due to meningococcal infection and began to receive ceftriaxone (CTRX). Gonococci were detected in a venous blood culture a few days later, and this case was diagnosed as DGI. CTRX was effective, and the patient was discharged. However, four weeks later, he complained of the same subjective symptoms as at the beginning and was hospitalized again. The presence of gonococcus was proven by venous blood culture, CTRX was re-administered and the patient responded. After discharge, he was counseled on safer sexual activity, including accurate and consistent use of condoms, by urologists. He has not relapsed with DGI for more than one year. When serious signs of infection occur in patients receiving eculizumab, it is recommended to consider DGI as well as invasive meningococcal infection, and CTRX should be given.Keywords: disseminated gonococcal infection, DGI, eculizumab, paroxysmal nocturnal hemoglobinuria, PNH, ceftriaxone

Makoto Saito,1 Kencho Miyashita,2 Yosuke Miura,3 Reiki Ogasawara,1 Minoru Kanaya,1 Koh Izumiyama,1 Akio Mori,1 Takeshi Kondo,1 Masanori Tanaka,1 Masanobu Morioka,1 Shinya Tanaka4 1Department of Internal Medicine and Hematology, Aiiku Hospital, Sapporo, Japan; 2Department of Gastroenterology, Aiiku Hospital, Sapporo, Japan; 3Department of Internal Medicine, Megumino Hospital, Eniwa, Japan; 4Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan Abstract: Colorectal follicular lymphoma (FL) occurs less frequently than duodenal-type FL, which is an established entity, and primary multiple FL only involving the colon is rare. Furthermore, the coexistence of lymphoma and multiple myeloma (MM) within the same patient is rare and the current study reports such a case. The patient was an asymptomatic 62-year-old man. He underwent colonoscopy screening, which revealed at least five polypoid tumors from the cecum to the rectum. Biopsy samples stained positive for CD20 and B-cell lymphoma 2 (BCL2) but stained negative for CD10, and fluorescence in situ hybridization analysis identified IGH/BCL2 in 95.2% of the tumor cells. Based on these findings, the patient was diagnosed with FL. On the bone marrow aspirate, the plasma cell count was 30% of all nucleated cells. Bence-Jones κ-type protein was detected by protein electrophoresis in serum and urine. The serum-free light chain κ/λ level was significantly elevated (484.3). Thus, the patient was also diagnosed with MM. Both FL and MM were targeted therapeutically; rituximab and bendamustine were effective for FL, and lenalidomide and low-dose dexamethasone were effective for MM. The patient was treated for 3 years and 7 months and, until now, was off-treatment for 4 years without rapid progression of the two malignancies. Although both diseases are still present, the patient has maintained stable disease. Our findings suggest that lymphoma and MM should be targeted separately as independent hematological malignancies when they occur concurrently. Keywords: follicular lymphoma, colon, multiple myeloma, coexistence, treatment

Although high-intensity resistance training (RT) increases arterial stiffness, removing weightlifting stimuli returns arterial stiffness to baseline levels within relatively short periods during 4-8 weeks. This study investigates the effects of repeated RT cessation and resumption on arterial stiffness. Eighteen young healthy subjects were randomly assigned to a group that performed continuous RT (CRT, n = 9) and a group that performed periodic RT (PRT, n = 9). Both groups performed RT at 75% of one repetition maximum for 3 days per week. The CRT group continuously trained for 16 weeks, whereas the PRT group performed 3 cycles of 4 weeks training, with 2 weeks detraining intervals between cycles. The carotid-femoral pulse wave velocity in the CRT group significantly increased (P<0.05) at 4, 6, 10, 12, 16 and 20 weeks from baseline, whereas in the PRT group it significantly increased (P<0.05) after 4, 10 and 16 weeks from baseline, and was significantly lower (P<0.05) than that of the CRT group after 6,10,12,16 and 20 weeks. Muscle mass and strength in the both groups significantly increased after 16 weeks from baseline and persisted for 20 weeks (P<0.05). These results suggest that PRT, including short-term repeated cessation and resumption, attenuates increases in arterial stiffness. [ABSTRACT FROM AUTHOR]

Genetic strain-dependent reactivity to mechanical stimuli in rat skeletal muscle has not been examined. This study aimed to examine whether genetic strain-dependency is associated with reactivity in protein metabolism and the resultant muscle hypertrophy after isometric resistance training (RT). The right triceps of Sprague-Dawley (SD) and Wistar rats underwent 12 sessions of RT. After RT, a transition from the IIb to the IIx myosin heavy-chain isoform was observed in both strains. In SD rats, the lateral gastrocnemius muscle (LG) mass of the trained legs (TRN) was significantly higher than that of the control legs (CON) (7.8 %, P<0.05). Meanwhile, in Wistar rats, the LG mass was unchanged. In SD rats, the levels of 70-kDa ribosomal protein S6 kinase (p70S6k) and forkhead box 3a (FOXO3a) phosphorylation in the TRN were significantly greater than those of the CON (2.2- and 1.9-fold, respectively; P<0.05). The expression of muscle ring finger-1 (MuRF1) and muscle atrophy F-box (MAFbx/atrogin-1) in the TRN was significantly lower than those of the CON (0.6- and 0.7-fold, respectively; P<0.05). However, in Wistar rats, there was no significant difference. These results suggest a genetic strain difference in protein metabolism. This phenomenon may be useful for studying individual differences in response to RT. [ABSTRACT FROM AUTHOR]

Tropospheric motions can be inferred from geostationary satellites by tracking clouds and water vapor in sequential imagery. These atmospheric motion vectors (AMV) have been operationally assimilated into global models for the past three decades, with positive forecast impacts. This paper presents results from a study to assess the impact of AMV derived from Geostationary Operational Environmental Satellite (GOES) imagery on mesoscale forecasts over the conventional data-poor central North Pacific region. These AMV are derived using the latest automated processing methodologies by the University of Wisconsin—Cooperative Institute for Meteorological Satellite Studies (CIMSS). For a test case, a poorly forecast subtropical cyclone (kona low) that occurred over Hawaii on 23–27 February 1997 was chosen. The Local Analysis and Prediction System (LAPS) was used to assimilate GOES-9 AMV data and to produce fifth-generation Pennsylvania State University–NCAR Mesoscale Model (MM5) initial conditions. The satellite wind assimilation is carried out on the 27-km-resolution domain covering the central Pacific area. The MM5 was run with three two-way nested domains (27, 9, and 3 km), with the innermost domain moving with the kona low. The AMV data are found to influence the cyclone’s development, improving the prediction of the cyclone’s central pressure and the track of the low’s center. Since September 2003, GOES-10 AMV data have been routinely accessed from CIMSS in real time and assimilated into the University of Hawaii (UH) LAPS, providing high-resolution initial conditions for twice-daily runs of MM5 at the Mauna Kea Weather Center collocated at the UH. It is found that the direct assimilation of AMV data into LAPS has a positive impact on the forecast accuracy of the UH LAPS/MM5 operational forecasting system when validated with observations in Hawaii. The implications of the results are discussed. [ABSTRACT FROM AUTHOR]

In this paper, we report solar neutron events detected in the solar cycle 23, especially three interesting events detected on November 23rd and 28th 1998 in Tibet and October 28th 2003 in Tsumeb. [ABSTRACT FROM AUTHOR]

The article discusses research done on the effect of acute and chronic resistance exercise on mitochondrial function and morphology in rat skeletal muscle.

Abstract: The Sun was intensely active from late October to the beginning of November 2003. A series of 11 X class solar flares occurred in NOAA regions 484, 486 and 488. Unique among this series of flares were those occurring on November 2 and 4 in which solar neutrons were observed by the ground based neutron monitors located at Mt. Chacaltaya, Bolivia and Haleakala, Hawaii, respectively. In these flares, intense emission of hard X-rays and γ-rays have been observed by the satellites. It seems that production of solar neutrons coincided with the production of the hard electromagnetic radiations of these two flares. [Copyright &y& Elsevier]

A patient undergoing cord blood transplantation for refractory angioimmunoblastic T-cell lymphoma was subsequently managed with long-term immunosuppressants for chronic graft-versus-host disease (GVHD). On day 591 post-transplant, she exhibited disorientation and cognitive dysfunction. Magnetic resonance imaging (MRI) of the brain revealed two hyperintense foci in the white matter, suggestive of progressive multifocal leukoencephalopathy (PML). However, we did not include PML in the differential diagnosis at that time. Unfortunately, she developed progressive cognitive impairment, and repeated brain MRIs showed a progression in lesion size. She was still taking immunosuppressants to control her GVHD, therefore we suspected PML. The diagnosis of PML was confirmed through the detection of a John Cunningham (JC) virus in the cerebrospinal fluid on day 640 post-transplant. This report highlights the critical need to consider PML in differential diagnoses for post-allogeneic transplant patients, especially those who exhibit progressive neurological symptoms while on prolonged immunosuppressant therapy., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Information regarding follow-up duration after treatment for newly diagnosed diffuse large B-cell lymphoma (DLBCL) is important. However, a clear endpoint has yet to be established. We totally enrolled 2182 patients newly diagnosed with DLBCL between 2008 and 2018. The median age of the patients was 71 years. All patients were treated with rituximab- and anthracycline-based chemotherapies. Each overall survival (OS) was compared with the age- and sex-matched Japanese general population (GP) data. At a median follow-up of 3.4 years, 985 patients experienced an event and 657 patients died. Patients who achieved an event-free survival (EFS) at 36 months (EFS36) had an OS equivalent to that of the matched GP (standard mortality ratio [SMR], 1.17; P=0.1324), whereas those who achieved an EFS24 did not have an OS comparable to that of the matched GP (SMR, 1.26; P=0.0095). Subgroup analysis revealed that relatively old patients (>60 years), male patients, those with limited-stage disease, those with a good performance status, and those with low levels of soluble interleukin 2 receptor already had a comparable life expectancy to the matched GP at an EFS24. In contrast, relatively young patients had a shorter life expectancy than matched GP, even with an EFS36. In conclusion, an EFS36 was shown to be a more suitable endpoint for newly diagnosed DLBCL patients than an EFS24. Of note, younger patients require a longer EFS period than older patients in order to obtain an equivalent life expectancy to the matched GP.

Abstract: Graft-versus-host disease (GVHD) is the major obstacle to performing allogeneic hematopoietic cell transplantation (allo-HCT). We and others have shown that intestinal stem cells are targeted in lower gastrointestinal GVHD. A leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5)-expressing gastric stem cells (GSCs) reside at the base of the gastric glands in mice. After experimental allo-HCT, Lgr5+ GSCs significantly decreased. Parietal cells, which underwent continuous renewal by GSCs, were injured in gastric GVHD, leading to failure of gastric acidification and aerobic bacterial overgrowth in the duodenum. Fate-mapping analysis demonstrated that administration of R-Spondin1 (R-Spo1) that binds to Lgr5 for 6 days in naïve mice significantly increased proliferating epithelial cells derived from Lgr5+ GSCs. R-Spo1 administered on days -3 to -1 and from days +1 to +3 of allo-HCT protected GSCs, leading to amelioration of gastric GVHD and restoration of gastric acidification, and suppression of aerobic bacterial overgrowth in the duodenum. In conclusion, Lgr5+ GSCs were targeted by gastric GVHD, resulting in disruption of the gastric homeostasis, whereas R-Spo1 protected Lgr5+ GSCs from GVHD and maintained homeostasis in the stomach., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objective The prognosis of the patients who relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is poor, and therapeutic options are limited. In the present study, we investigated the efficacy and factors associated with the survival in patients with acute leukemia or myelodysplastic syndrome (MDS) who relapsed following allo-HSCT and were treated with donor lymphocyte infusion (DLI) in real-world practice. Patients Twenty-nine patients with acute myeloid leukemia 21 , acute lymphoid leukemia 4 or MDS 4 were enrolled. Eleven patients were diagnosed with hematological relapse, and 18 were diagnosed with molecular or cytogenetic relapse. Results The median injection number and median total number of infused CD3 + T cells were 2 and 5.0×10 7 /kg, respectively. The cumulative incidence of acute graft-versus-host disease (aGVHD) of grade ≥II at 4 months after the initiation of DLI was 31.0%. Extensive chronic graft-versus-host disease (cGVHD) occurred in 3 (10.3%) patients. The overall response rate was 51.7%, including 3 cases of hematological complete remission (CR) and 12 cases of molecular/cytogenetic CR. Cumulative relapse rates at 24 and 60 months following DLI in patients who achieved CR were 21.4% and 30.0%, respectively. The overall survival rates at 1, 2 and 3 years after DLI were 41.4%, 37.9% and 30.3%, respectively. Molecular/cytogenetic relapse, a longer interval from HSCT to relapse, and concomitant chemotherapy with 5-azacytidine (Aza) were significantly associated with a relatively long survival following DLI. Conclusion These results indicated that DLI was beneficial for patients with acute leukemia or MDS who relapsed after allo-HSCT and suggested that DLI in combination with Aza for molecular or cytogenetic relapse might result in favorable outcomes.

Hodgkin lymphoma type of Richter syndrome (HL-type RS) is a rare disease that arises in patients with chronic lymphocytic leukemia (CLL). HL-type RS lesions can manifest in various sites and are often accompanied by related symptoms. This is the first case report to describe diagnosis of HL-type RS after emergency surgery for gastrointestinal perforation caused by the development of a HL-type RS lesion. A 47-year-old man diagnosed with CLL three years prior began treatment with ibrutinib due to worsening anemia and splenomegaly two months prior to the emergency department presentation. Although splenomegaly improved, lymphocytopenia, anemia, and a newly arising mesenteric lymphadenopathy continued to worsen. He presented to the emergency department with abdominal pain, and subsequent surgery revealed small intestinal perforation and mesenteric lymphadenopathy with HL-type RS confirmed by histopathological examination of the resected small intestine. He subsequently received brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A + AVD), which effectively managed the HL-type RS. If CLL clinical presentation deviates from the typical course, an early tissue biopsy should be considered to evaluate for HL-type RS. Given the adoption of the A + AVD regimen as the standard treatment for Hodgkin lymphoma, further research is needed to evaluate its efficacy in HL-type RS., (© 2023. Japanese Society of Hematology.)

Objectives: The cryptic fusion oncogene NUP98::NSD1 is known to be associated with FLT3-ITD mutation in acute myeloid leukemia (AML), and an independent poor prognostic factor in pediatric AML. However, there are little data regarding the clinical significance of NUP98::NSD1 in adult cohort., Methods: We conducted a multicenter retrospective study to investigate the prevalence, clinical characteristics, and prognostic impact of NUP98::NSD1 in adult FLT3-ITD-positive AML patients., Results: In a total of 97 FLT3-ITD-positive AML patients, six cases (6.2%) were found to harbor the NUP98::NSD1 fusion transcript. NUP98::NSD1 positive cases had significantly higher platelet counts and a higher frequency of FAB-M4 morphology than NUP98::NSD1 negative cases. NUP98::NSD1 was found to be mutually exclusive with NPM1 mutation, and was accompanied by the WT1 mutation in three of the six cases. The presence of NUP98::NSD1 fusion at the time of diagnosis predicted poor response to cytarabine-anthracycline-based intensive induction chemotherapy (induction failure rate: 83% vs. 36%, p = .038). Five of the six cases with NUP98::NSD1 underwent allogeneic hematopoietic stem cell transplantation (HSCT). Two of the five cases have successfully maintained remission, with one of them being rescued through a second HSCT., Conclusions: Detecting NUP98::NSD1 in adult FLT3-ITD-positive AML is crucial to recognizing chemotherapy-resistant group., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Mechanisms underlying mechanical overload-induced skeletal muscle hypertrophy have been extensively researched since the landmark report by Morpurgo (1897) of "work-induced hypertrophy" in dogs that were treadmill trained. Much of the preclinical rodent and human resistance training research to date supports that involved mechanisms include enhanced mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling, an expansion in translational capacity through ribosome biogenesis, increased satellite cell abundance and myonuclear accretion, and postexercise elevations in muscle protein synthesis rates. However, several lines of past and emerging evidence suggest that additional mechanisms that feed into or are independent of these processes are also involved. This review first provides a historical account of how mechanistic research into skeletal muscle hypertrophy has progressed. A comprehensive list of mechanisms associated with skeletal muscle hypertrophy is then outlined, and areas of disagreement involving these mechanisms are presented. Finally, future research directions involving many of the discussed mechanisms are proposed.

Neurolymphomatosis (NL) is a rare clinical entity characterized by lymphomatous infiltration of the peripheral nervous system. According to recent retrospective data, consolidative high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) may be beneficial for NL. However, few reports to date have discussed optimal conditioning regimens. Herein, we report two cases of NL in patients with relapsed intravascular large B-cell lymphoma who received consolidative thiotepa-containing HDC-ASCT. Case 1: A 56-year-old woman who relapsed 2 months after the first complete remission (CR) and underwent ASCT. Case 2: A 65-year-old woman who relapsed 8 months after the first CR and underwent ASCT. Both patients engrafted. Time to neutrophil engraftment was 10 and 12 days after HDC-ASCT, and CR was sustained for 26 and 18 months, respectively, as of the last follow-up. Although there is little evidence supporting the utility of thiotepa-based HDC-ASCT in patients with NL, the results of this case report suggest that further studies are warranted to determine its efficacy in this setting., (© 2023. Japanese Society of Hematology.)

Next-generation sequencing of AML has identified specific genetic mutations in AML patients. Hematologic Malignancies (HM)-SCREEN-Japan 01 is a multicenter study to detect actionable mutations using paraffin-embedded bone marrow (BM) clot specimens rather than BM fluid in AML patients for whom standard treatment has not been established. The purpose of this study is to evaluate the presence of potentially therapeutic target gene mutations in patients with newly diagnosed unfit AML and relapsed/refractory AML (R/R-AML) using BM clot specimens. In this study, 188 patients were enrolled and targeted sequencing was undertaken on DNA from 437 genes and RNA from 265 genes. High-quality DNA and RNA were obtained using BM clot specimens, with genetic alterations successfully detected in 177 patients (97.3%), and fusion transcripts in 41 patients (23.2%). The median turnaround time was 13 days. In the detection of fusion genes, not only common fusion products such as RUNX1-RUX1T1 and KMT2A rearrangements, but also NUP98 rearrangements and rare fusion genes were observed. Among 177 patients (72 with unfit AML, 105 with R/R-AML), mutations in KIT and WT1 were independent factors for overall survival (hazard ratio = 12.6 and 8.88, respectively), and patients with high variant allele frequency (≥40%) of TP53 mutations had a poor prognosis. As for the detection of actionable mutations, 38% (n = 69) of patients had useful genetic mutation (FLT3-ITD/TKD, IDH1/2, and DNMT3A R822 ) for treatment selection. Comprehensive genomic profiling using paraffin-embedded BM clot specimens successfully identified leukemic-associated genes that can be used as therapeutic targets., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The purpose of this study was to investigate whether aging alters the effect of nutritional status on contraction-induced muscle protein metabolism. In an overnight fasted or fed states, the right gastrocnemius muscle of young (3 months) and aged (24 months) male C57BL/6J mice was isometrically contracted via percutaneous electrical stimulation. The left gastrocnemius muscle served as a control. In the fasted state, there were no differences in basal or contraction-induced muscle protein synthesis between young and old mice. However, in the fed state, basal muscle protein synthesis was greater in young mice, and contraction increased muscle protein synthesis only in young mice. In the fed state, although phosphorylation of 4E-BP1 was similarly increased by contraction in both ages, the increase in phosphorylation of p70S6K was greater in young mice. Our results indicate that aging impairs the ability to integrate signals from muscle contraction and nutrition, leading to aging-induced anabolic resistance to muscle contraction in the postprandial state., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Adult T-cell leukemia/lymphoma (ATLL) is one of the aggressive peripheral T-cell neoplasms with a poor prognosis. Accumulating evidence demonstrates that escape from adaptive immunity is a hallmark of ATLL pathogenesis. However, the mechanisms by which ATLL cells evade natural killer (NK)-cell-mediated immunity have been poorly understood. Here we show that CD48 expression in ATLL cells determines the sensitivity for NK-cell-mediated cytotoxicity against ATLL cells. We performed unbiased genome-wide clustered regularly interspaced short palindromic repeat (CRISPR) screening using 2 ATLL-derived cell lines and discovered CD48 as one of the best-enriched genes whose knockout conferred resistance to YT1-NK cell line-mediated cytotoxicity. The ability of CD48-knockout ATLL cells to evade NK-cell effector function was confirmed using human primary NK cells with reduced interferon-γ (IFNγ) induction and degranulation. We found that primary ATLL cells had reduced CD48 expression along with disease progression. Furthermore, other subgroups among aggressive peripheral T-cell lymphomas (PTCLs) also expressed lower concentrations of CD48 than normal T cells, suggesting that CD48 is a key molecule in malignant T-cell evasion of NK-cell surveillance. Thus, this study demonstrates that CD48 expression is likely critical for malignant T-cell lymphoma cell regulation of NK-cell-mediated immunity and provides a rationale for future evaluation of CD48 as a molecular biomarker in NK-cell-associated immunotherapies., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

In forensic medicine, although various alcohols have been reported as indicators of decomposition in collected blood, no studies have examined short-chain fatty acids as indicators. In this study, the blood n-butyric acid concentration was quantified, and the association between n-butyric acid and decomposition was investigated to determine whether the detection of n-butyric acid could be a new indicator of decomposition. Among the forensic autopsies performed from 2016 to 2018 in our laboratory, the cases were divided into decomposed (n = 20) and non-decomposed (n = 20) groups based on macroscopic findings. Blood samples collected at the time of autopsy were derivatized with 3-nitrophenylhydrazine hydrochloride after solid-phase extraction. The n-butyric acid concentration was measured using liquid chromatography-tandem mass spectrometry. In addition, ethanol and n-propanol were measured using a gas chromatography-flame ionization detector. There was a significant difference (p < 0.01) in the concentrations of n-butyric acid between the decomposed and non-decomposed groups (0.343 ± 0.259 [0.030-0.973] and 0.003 ± 0.002 [0.001-0.007] mg/mL, respectively). In the decomposed group, n-butyric acid was detected at high concentrations, even in cases where n-propanol was low. These results suggest that n-butyric acid is more likely to be an indicator of blood decomposition than n-propanol., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Hawaii is a multicultural state with many different ethnicities, including Native Hawaiians and other Pacific Islanders (NHOPI). This demographic has not been thoroughly studied, despite its significantly higher prevalence of stroke. This study aimed to characterize risk factors for ischemic stroke in NHOPI compared to other ethnicities., Methods: An Institutional Review Board (IRB) sanctioned retrospective chart review was conducted at a multi-site community neurology clinic from June 2017 through June 2019. Prospective patients were identified from the database using the International Classification of Diseases 10th Edition (ICD-10) codes for ischemic stroke. 326 patients (99 NHOPI, 116 Asian, 111 Caucasian) with a history of ischemic stroke met the inclusion criteria. Risk factors were determined based on the American Stroke Association guidelines; ethno-racial grouping was based on self-identification; and average household income levels were estimated based on patient zip codes US Census Bureau data. Continuous variable risk factors were analyzed using an analysis of variance (ANOVA) and post-hoc pairwise comparisons using Tukey-Kramer; a multivariate analysis was conducted., Results: Compared to Asians and Caucasians, NHOPI patients were on average 11 years younger at the onset of stroke and more likely to be women. The NHOPI group also had the highest rates of diabetes and obesity. NHOPI average income was significantly lower compared to the Caucasian group. Hypertension and hyperlipidemia were found to be higher in the Asian population. Alcohol consumption was reported more frequently among Caucasian patients., Conclusions: These results better-characterized risk factors for ischemic stroke among NHOPI in Hawaii. The younger age of stroke onset in NHOPI patients is likely due to the higher burden of cardiovascular risk factors like obesity, smoking, and diabetes. Identifying such disparities in associated risk for NHOPI and other ethnicities can allow targeted stroke prevention and outpatient care in a multicultural setting., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Azacitidine (AZA) improves overall survival (OS) in patients with high-risk myelodysplastic syndromes (MDS). However, predictive factors for response to AZA remain largely unknown. To elucidate whether dynamic change in peripheral blood (PB) Wilms' Tumor 1 (WT1) mRNA levels could predict response to AZA, we retrospectively identified 75 treatment-naïve patients with high-risk MDS who received at least 3 cycles of AZA. We classified patients into 4 groups, low-increase (LI), low-stable (LS), high-decrease (HD), and high-stable (HS) based on the dynamic change in PB WT1 mRNA levels within 3 cycles of AZA. Cumulative incidence of overall response after 10 cycles of AZA was significantly higher in LS/HD than in HS/LI (75.5% vs 4.5%, P < 0.001). The median OS for LS/HD was 18.2 months (95% CI, 12.8-28.1 months), whereas it was 11.6 months for HS/LI (95% CI, 6.6-14.1 months; P < 0.001). Multivariate analysis demonstrated that poor-/very poor-IPSS-R cytogenetic risk and HS/LI were independently associated with poor OS (poor-/very poor-IPSS-R cytogenetic risk: HR, 2.26; 95% CI, 1.10-4.68, P = 0.03, HS/LI: HR, 2.32; 95% CI, 1.21-4.46, P = 0.01). Patients with HS/LI did not show any further response to continuous AZA, and they should be considered for alternative therapy from earlier cycles., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Evans syndrome presents as concurrent autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP). Systemic lupus erythematosus (SLE) is the most frequent autoimmune disorder associated with Evans syndrome. We herein report a case of new-onset Evans syndrome associated with SLE after BNT162b2 mRNA coronavirus disease 2019 (COVID-19) vaccination in a 53-year-old woman. Blood examination at diagnosis showed hemolytic anemia with a positive Coombs test and thrombocytopenia. Hypocomplementemia and the presence of lupus anticoagulant indicated a strong association with SLE. Prednisolone administration rapidly restored hemoglobin level and platelet count. This case suggests that mRNA COVID-19 vaccination may cause an autoimmune disorder. Physicians should be aware of this adverse reaction by mRNA COVID-19 vaccination and should consider the benefits and risks of vaccination for each recipient., (© 2021. Japanese Society of Hematology.)

Angiogenesis and muscle satellite cell (SC)-mediated myonuclear accretion are considered essential for the robust response of contraction-induced muscle hypertrophy. Moreover, both myonucleus and SCs are physically adjacent to capillaries and are the major sites for the expression of proangiogenic factors, such as VEGF, in the skeletal muscle. Thus, events involving the addition of new myonuclei via activation of SCs may play an important role in angiogenesis during muscle hypertrophy. However, the relevance among myonuclei number, capillary supply, and angiogenesis factor is not demonstrated. The Notch effector HeyL is specifically expressed in SCs in the skeletal muscle and is crucial for SC proliferation by inhibiting MyoD in overload-induced muscle hypertrophy. Here, we tested whether the addition of new myonuclei by SC in overloaded muscle is associated with angiogenic adaptation by reanalyzing skeletal muscle from HeyL-knockout (KO) mice, which show blunted responses of SC proliferation, myonucleus addition, and overload-induced muscle hypertrophy. Reanalysis confirmed blunted SC proliferation and myonuclear accretion in the plantaris muscle of HeyL-KO mice 9 wk after synergist ablation. Interestingly, the increase in capillary-to-fiber ratio observed in wild-type (WT) mice was impaired in HeyL-KO mice. In both WT and HeyL-KO mice, the expression of VEGFA and VEGFB was similarly increased in response to overload. In addition, the expression pattern of TSP-1, a negative regulator of angiogenesis, was also not changed between WT and HeyL-KO mice. Collectively, these results suggest that SCs activation-myonuclear accretion plays a crucial role in angiogenesis during overload-induced muscle hypertrophy via independent of angiogenesis regulators.

In this real-world clinical study, in which we determined eligibility for allogenic hematopoietic stem cell transplantation by prognostic factors and minimal residual disease status, we retrospectively evaluated cytogenetic, genetic, and clinical features in 96 patients with core-binding factor acute myeloid leukemia (CBF-AML) including 62 patients with RUNX1/RUNX1T1 and 34 patients with CBFβ/MYH11. Multivariate analyses for 5-year overall survival (OS) in CBF-AML patients revealed that age of 50 years or older (HR: 3.46, 95% CI 1.47-8.11, P = 0.004) and receiving 2 or more induction cycles (HR: 3.55, 95% CI 1.57-8.05, P = 0.002) were independently associated with worse OS and that loss of sex chromosome (LOS) was independently associated with better OS (HR: 0.09, 95% CI 0.01-0.71, P = 0.022). At the time of complete remission, all 21 karyotyped patients with LOS had a normal karyotype. Furthermore, in all 9 patients with LOS who had a mosaic of metaphase cells with and without t(8;21) or inv(16), the metaphase cells without t(8;21)/inv(16) showed a normal karyotype. These results proved that LOS was not age-related and physiological, but rather a neoplastic chromosomal abnormality., (© 2021. Japanese Society of Hematology.)

Background: The WHO's Health Promoting Schools (HPS) framework is based on an understanding of the reciprocal relationship between health and education, and the need to take a holistic approach to health promotion in schools. We aim to clarify the degree to which the HPS framework is reflected in the national policies of eight target countries and the issues surrounding its successful implementation., Methods: Date were collected through two expert workshops with participants from eight Asian countries: Cambodia, China, Japan, Korea, Lao PDR, Nepal, the Philippines, and Thailand. In the first workshop, data collected on national policy were mapped against the HPS framework. From this, key issues were identified, and follow-up data collection was conducted in each country for a second workshop., Results: We identified a policy shift toward the HPS framework in six out of the eight countries. Neither Japan nor Korea had changed their national policy frameworks to reflect an HPS approach; however, in the latter, model programs had been introduced at a local level. We identified various barriers to successful implementation, especially in relation to mental health and wellbeing., Conclusion: Given the recent shift toward the HPS approach in six out of the eight countries in this study, there is a need to conduct research to assess the impact of this framework on the health and wellbeing of students and school staff. At the same time, we call for more dialog in the context of Japan to explore the possible benefits of introducing the HPS framework into schools., (© 2022 The Authors. Pediatrics International published by John Wiley & Sons Australia, Ltd on behalf of Japan Pediatric Society.)

Fms-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in acute myelogenous leukemia (AML) and the mutation is associated with poor prognosis of patients. Two distinct types of activating mutations have been identified in AML samples. One is internal tandem duplications in the juxtamembrane domain ( FLT3 -ITD) and the other is point mutations in the tyrosine kinase domain ( FLT3 -TKD). Gilteritinib is a FLT3 inhibitor that inhibits both FLT3-ITD and FLT3-TKD. It was reported that differentiation of leukemic blasts accompanied by differentiation syndrome occurs in some patients treated with gilteritinib. However, information about the precise clinical course is limited, and appropriate management of differentiation syndrome has not been established. We report a case of relapsed AML with FLT3 -ITD that was treated with gilteritinib. Analysis of the FLT3- ITD variant allele frequency (VAF) revealed that FLT3 -ITD VAF was not decreased despite achievement of complete remission with incomplete hematologic recovery. Remarkable increases of monocytes and granulocytes accompanied by differentiation syndrome were observed at 6 months after the initiation of gilteritinib treatment. Intermittent chemotherapy with low-dose cytarabine and mitoxantrone was effective for reducing myelomonocytosis and resolving differentiation syndrome.

Objectives: We aimed to investigate the effect of iron deficiency on basal- and contraction-induced increases in muscle protein synthesis., Methods: Four-wk-old male Sprague-Dawley rats were divided into three groups. The rats in two of the three groups had free access to a control diet (AD) or iron-deficient diet (ID) for 4 wk. The rats in the third group (CON) were pair-fed the control diet to the mean intake of the ID group., Results: In comparison with the CON group, the ID group showed significantly lower hematocrit and hemoglobin concentrations, iron-containing protein levels, and total iron content in skeletal muscle, but non-iron-containing protein levels did not show any differences between the groups. Protein synthesis, measured by puromycin-labeled peptides, was lower in the ID group compared with the CON group in both basal- and contraction-stimulated states. The ID diet impaired the activation levels of signaling pathways involved in protein synthesis, such as ribosomal protein S6 and eukaryotic translation initiation factor 4E-binding protein 1. Furthermore, dietary iron deficiency decreased autophagy capacity, but did not affect the ubiquitinated protein content., Conclusions: These results suggest that severe iron deficiency decreases not only basal but also muscle contraction-induced increases in protein synthesis due to, at least in part, downregulation of the protein synthesis signaling pathway in the skeletal muscle., (Copyright © 2021 Elsevier Inc. All rights reserved.)

High-intensity muscle contractions (HiMCs) are known to increase c-Myc expression that is known to stimulate ribosome biogenesis and protein synthesis in most cells. However, although c-Myc mRNA transcription and c-Myc mRNA translation have been shown to be upregulated following resistance exercise concomitantly with increased ribosome biogenesis, this connection has not been tested directly. We investigated the effect of adeno-associated virus (AAV)-mediated c-Myc overexpression, with or without fasting or percutaneous electrical stimulation-induced HiMC, on ribosome biogenesis and protein synthesis in adult mouse skeletal muscles. AAV-mediated overexpression of c-Myc in mouse skeletal muscles for 2 wk increased the DNA polymerase subunit POL1 mRNA, 45S-pre-rRNA, total RNA, and muscle protein synthesis without altering mechanistic target of rapamycin complex 1 (mTORC1) signaling under both ad libitum and fasted conditions. RNA-sequencing (RNA-seq) analyses revealed that c-Myc overexpression mainly regulated ribosome biogenesis-related biological processes. The protein synthesis response to c-Myc overexpression mirrored the response with HiMC. No additional effect of combining c-Myc overexpression and HiMC was observed. Our results suggest that c-Myc overexpression is sufficient to stimulate skeletal muscle ribosome biogenesis and protein synthesis without activation of mTORC1. Therefore, the HiMC-induced increase in c-Myc may contribute to ribosome biogenesis and increased protein synthesis following HiMC. NEW & NOTEWORTHY Resistance exercise is known to increase c-Myc expression, which is known to stimulate ribosome biogenesis and protein synthesis in a variety of cells. However, whether the increase in c-Myc stimulates ribosome biogenesis and protein synthesis in skeletal muscles remains unknown. We found that c-Myc overexpression is sufficient to stimulate skeletal muscle ribosome biogenesis and protein synthesis without activation of mTORC1.

Chronic obesity and insulin resistance are considered to inhibit contraction-induced muscle hypertrophy, through impairment of mammalian target of rapamycin complex 1 (mTORC1) and muscle protein synthesis (MPS). A high-fat diet is known to rapidly induce obesity and insulin resistance within a month. However, the influence of a short-term high-fat diet on the response of mTORC1 activation and MPS to acute resistance exercise (RE) is unclear. Thus the purpose of this study was to investigate the effect of a short-term high-fat diet on the response of mTORC1 activation and MPS to acute RE. Male Sprague-Dawley rats were randomly assigned to groups and fed a normal diet, high-fat diet, or pair feed for 4 wk. After dietary habituation, acute RE was performed on the gastrocnemius muscle via percutaneous electrical stimulation. The results showed that 4 wk of a high fat-diet induced intramuscular lipid accumulation and insulin resistance, without affecting basal mTORC1 activity or MPS. The response of RE-induced mTORC1 activation and MPS was not altered by a high-fat diet. On the other hand, analysis of each fiber type demonstrated that response of MPS to an acute RE was disappeared specifically in type I and IIa fiber. These results indicate that a short-term high-fat diet causes anabolic resistance to acute RE, depending on the fiber type. NEW & NOTEWORTHY A high-fat diet is known to rapidly induce obesity, insulin resistance, and anabolic resistance to nutrition within a month. However, the influence of a short-term high-fat diet on the response of muscle protein synthesis to acute resistance exercise is unclear. We observed that a short-term high-fat diet causes obesity, insulin resistance, intramuscular lipid droplet accumulation, and anabolic resistance to resistance exercise specifically in type I and IIa fibers.

Skeletal muscle has numerous nuclei within a cell. The nucleus is considered as the central organelle for muscle protein synthesis (MPS). However, it is unclear whether myonuclear number is associated with MPS capacity within the individual muscle fibres. Therefore, the purpose of the present study was to reveal the relationship between myonuclear number per unit muscle fibre length and MPS under basal and conditions of elevated MPS by high-intensity muscle contraction (HiMC) using an in vivo nascent protein labelling technique (SUnSET) in rodents. We found that myonuclear number was positively correlated with MPS in individual muscle fibres in the basal condition. Similarly, ribosomal protein S6 (rpS6) content, which is a rough estimate of ribosome content, was positively correlated with MPS. However, myonuclear number was not associated with rpS6 content. In contrast to the basal condition, when MPS was increased by acute HiMC, no correlation was observed between myonuclear number and MPS, but the association between rpS6 and MPS was maintained. Importantly, these observations indicate that the number of nuclei in individual myofibers is related only to MPS at rest. However, the ribosome content in individual fibres is related to MPS of individual myofibers both at rest and following HiMC., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Background: Glycolysis controls mTORC1 signaling and protein synthesis. In skeletal muscle, glucose metabolism increases with both exercise/contraction intensity and volume, and therefore, high-intensity muscle contraction (HiMC) such as resistance exercise facilitates glycolysis including glucose uptake and glycogen breakdown. However, it is unknown whether glycolysis regulates HiMC-induced mTORC1 activation and increase in protein synthesis., Methods: To determine whether glycolysis regulates basal and HiMC-induced mTORC1 signaling and protein synthesis, we employed 2-deoxyglucose (2-DG) to inhibit glycolysis and isometrically contracted the gastrocnemius muscle of Sprague Dawley rats using percutaneous electrical stimulation., Results: Inhibition of glycolysis by 2-DG inhibited basal phosphorylation of p70S6K and 4E-BP1 (downstream targets of mTORC1) and protein synthesis (all P < 0.05) independent of AMPK phosphorylation. AMPK phosphorylation was comparably increased after HiMC at 0 h post HiMC and returned to basal levels 6 h post HiMC in both vehicle- and 2-DG-treated groups. Glycolysis inhibition attenuated muscle contraction-induced phosphorylation of 4E-BP1 at 6 h post HiMC (P < 0.05) but not p70S6K phosphorylation and protein synthesis., Conclusion: Although glycolysis is involved in basal but not HiMC-induced muscle protein synthesis, it regulates both basal and HiMC-induced mTORC1 signaling, and may play key roles in skeletal muscle adaptation to HiMC., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)